TY - JOUR
T1 - An analog of withaferin a activates the MAPK and glutathione "stress" pathways and inhibits pancreatic cancer cell proliferation
AU - Liu, Xiaobing
AU - Qi, Wenqing
AU - Cooke, Laurence S.
AU - Kithsiri Wijeratne, E. M.
AU - Xu, Ya Ming
AU - Marron, Marilyn T.
AU - Leslie Gunatilaka, A. A.
AU - Mahadevan, Daruka
N1 - Funding Information:
We wish to acknowledge financial support from the Arizona Biomedical Research Commission (No. 0804) and United States Department of Agriculture (No. 20073862518531; A.A.L. Gunatilaka). We also thank Dr. David Mount and Ann M. Manziello of the Arizona Cancer Center Bioinformatics Shared Service supported by AZCC grant (P30CA023074) for their help in designing and conducting the statistical analysis of gene expression profiling and the Genomics core facility (AZCC) for conducting the RT-PCR studies and Dr. Michael Berman for expert advice on pathway analysis.
PY - 2011/11/15
Y1 - 2011/11/15
N2 - Withaferin A (WA) (1) and two analogs [4-epi-withaferin A (2) and 4,27-diacetyl-4-epi-withaferin A (3)] were evaluated for antitumor activity in pancreatic cancer cells. IC50 for 1, 2, and 3 were 0.87, 0.45, and 0.29 μM (BxPC-3); 1.28, 1.53, and 0.52 μM (MIAPaCa-2); and 0.59, 2.25, and 0.56 μM (PANC-1), respectively. We chose WA analog 3 for functional studies with confirmatory RT-PCR and Western blotting. ANOVA identified 33 (MIAPaCa-2), 54 (PANC-1), and 48 (BxPC-3) gene expression changes. Fisher exact test demonstrated MAPK and glutathione pathways to be overexpressed with WA analog 3. WA analog 3 elicits a dose-and time-dependent apoptosis, activates MAPK and glutathione "stress" pathways, and inhibits proliferation.
AB - Withaferin A (WA) (1) and two analogs [4-epi-withaferin A (2) and 4,27-diacetyl-4-epi-withaferin A (3)] were evaluated for antitumor activity in pancreatic cancer cells. IC50 for 1, 2, and 3 were 0.87, 0.45, and 0.29 μM (BxPC-3); 1.28, 1.53, and 0.52 μM (MIAPaCa-2); and 0.59, 2.25, and 0.56 μM (PANC-1), respectively. We chose WA analog 3 for functional studies with confirmatory RT-PCR and Western blotting. ANOVA identified 33 (MIAPaCa-2), 54 (PANC-1), and 48 (BxPC-3) gene expression changes. Fisher exact test demonstrated MAPK and glutathione pathways to be overexpressed with WA analog 3. WA analog 3 elicits a dose-and time-dependent apoptosis, activates MAPK and glutathione "stress" pathways, and inhibits proliferation.
KW - 4-Epi-withaferin A (2)
KW - 427-Diacetyl-4-epi-withaferin A (3)
KW - Apoptosis
KW - Gene expression profiling
KW - Glutathione pathway
KW - MAPK
KW - Pancreatic cancer
KW - Withaferin A (1)
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UR - http://www.scopus.com/inward/citedby.url?scp=81255203811&partnerID=8YFLogxK
U2 - 10.3109/07357907.2011.626478
DO - 10.3109/07357907.2011.626478
M3 - Article
C2 - 22085270
AN - SCOPUS:81255203811
SN - 0735-7907
VL - 29
SP - 668
EP - 675
JO - Cancer Investigation
JF - Cancer Investigation
IS - 10
ER -